1. Field of the invention
This invention relates to a process for preparing 2-oxindole compound, more particularly to a process which involves catalytically reacting isatin with hydrazine hydrate in a polar solvent in the presence of a weak base to form the 2-oxindole compound.
2. Description of the related art
Oxindoles, which have the following structure (structure I ): ##STR1## are known as an intermediate in making certain types of pharmaceutical related products, such as adibendan (structure II), a cardiotonic agent for congestive ##STR2## heart failure, which comprises an oxindole moiety (structure I ). Various tyrosine kinase inhibitors, which are useful for regulating epidermal growth, are also prepared from 2-oxindole. The 2-oxindole (structure III ) can be substituted or unsubstituted, and has the following structure: ##STR3## wherein R is an alkyl, alkoxyl, aryl, phenoxy, halogen, or hydrogen.
It has been known in the art that 2-oxindole can be prepared by a method (D. S. Soriano, J. Chem. Edu., 1993, 70, 332) illustrated by the following reaction: ##STR4## In this method, isatin (structure IV) is reacted with hydrazine hydrate in an anhydrous methanol to form an intermediate (i.e. indole hydrazone) in a suspended form in the reaction mixture. The intermediate is then separated from the reaction mixture and purified by crystallizing means. The purified intermediate is dried and subjected to the Wolf-Kishner reduction in an anhydrous ethanol solution in the presence of a strong base, such as sodium ethoxide, at an elevated temperature so as to yield the 2-oxindole product. The yield of the 2-oxindole obtained by this method can reach up to 69%.
The method described above is complicated because of its requirement for separating, purifying, and drying steps in the process of preparing the 2-oxindole. The method also requires the use of expansive anhydrous ethanol as solvent in the reaction mixture because sodium ethoxide can react with water and therefore lose its activity for catalyzing the reaction. In addition, this method uses a large amount of sodium ethoxide which is normally prepared by reacting sodium with anhydrous ethanol. Since sodium is extremely active and dangerous, the use of sodium ethoxide would give rise to safety concerns for this method.
Another method of preparing 2-oxindole is described by Crestini and Saladino, Synth. Commun. 1994, 24,2835, and is illustrated by the following reaction: ##STR5## In this method, isatin is first dissolved in pure hydrazine, and then reacted with pure hydrazine under heat to form the 2-oxindole product. The yield of the 2-oxindole obtained by this method can reach up to 76%.
The method described above requires the use of a large amount of pure hydrazine to dissolve the isatin for later reaction. It is known that pure hydrazine can cause severe explosion hazard when exposed to heat or reaction with oxidizers. Hence, the use of pure hydrazine requires extreme caution, which makes this method impractical.
Both methods described above are reported to use a high temperature of about 200.degree. C. for the reaction to take place. Such high temperature would consume much energy, and in the case that a strong base is used as a catalyst, results in the need of a reactor made from a special material for anti-corrosion purpose.